ArticleNucleic acids research2018
A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 43 citations in OpenAlex.
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- Structural and Mechanistic Insights into Atypical Bacterial Topoisomerase Inhibitors.ACS medicinal chemistry letters · 2025Article
- How Do Gepotidacin and Zoliflodacin Stabilize DNA-Cleavage Complexes with Bacterial Type IIA Topoisomerases? 2. A Single Moving Metal Mechanism.International journal of molecular sciences · 2024Article
- How Do Gepotidacin and Zoliflodacin Stabilize DNA Cleavage Complexes with Bacterial Type IIA Topoisomerases? 1. Experimental Definition of Metal Binding Sites.International journal of molecular sciences · 2024Article
- Structural insights into the assembly of type IIA topoisomerase DNA cleavage-religation center.Nucleic acids research · 2024Article
- Development of Novel Bacterial Topoisomerase Inhibitors Assisted by Computational Screening.ACS medicinal chemistry letters · 2024Article
- Navigating fluoroquinolone resistance in Gram-negative bacteria: a comprehensive evaluation.JAC-antimicrobial resistance · 2024Review
- Article
- The Importance of Substituent Position for Antibacterial Activity in the Group of Thiosemicarbazide Derivatives.Molecules (Basel, Switzerland) · 2024Article
- Antimicrobial Potential of Betulinic Acid and Investigation of the Mechanism of Action against Nuclear and Metabolic Enzymes with Molecular Modeling.Pathogens (Basel, Switzerland) · 2023Article
- What's on the Other Side of the Gate: A Structural Perspective on DNA Gate Opening of Type IA and IIA DNA Topoisomerases.International journal of molecular sciences · 2023Review
- Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin.Nature catalysis · 2023Article
- Design, Synthesis, Antibacterial Evaluations and In Silico Studies of Novel Thiosemicarbazides and 1,3,4-Thiadiazoles.Molecules (Basel, Switzerland) · 2022Article
- Towards Conformation-Sensitive Inhibition of Gyrase: Implications of Mechanistic Insight for the Identification and Improvement of Inhibitors.Molecules (Basel, Switzerland) · 2021Review
- Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.RSC medicinal chemistry · 2020Article
- Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance.Molecules (Basel, Switzerland) · 2020Review
- Identification of an ethyl 5,6-dihydropyrazolo[1,5-c]quinazoline-1-carboxylate as a catalytic inhibitor of DNA gyrase.Bioorganic & medicinal chemistry · 2020Article
- TEM Studies on Antibacterial Mechanisms of Black Phosphorous Nanosheets.International journal of nanomedicine · 2020Article
- Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation.Cell chemical biology · 2019Article
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Imidazopyrazinones (IPYs) are a new class of compounds that target bacterial topoisomerases as a basis for their antibacterial activity. We have characterized the mechanism of these compounds through structural/mechanistic studies showing they bind and stabilize a cleavage complex between DNA gyrase and DNA ('poisoning') in an analogous fashion to fluoroquinolones, but without the requirement for the water-metal-ion bridge. Biochemical experiments and structural studies of cleavage complexes of IPYs compared with an uncleaved gyrase-DNA complex, reveal conformational transitions coupled to DNA cleavage at the DNA gate. These involve movement at the GyrA interface and tilting of the TOPRIM domains toward the scissile phosphate coupled to capture of the catalytic metal ion. Our experiments show that these structural transitions are involved generally in poisoning of gyrase by therapeutic compounds and resemble those undergone by the enzyme during its adenosine triphosphate-coupled strand-passage cycle. In addition to resistance mutations affecting residues that directly interact with the compounds, we characterized a mutant (D82N) that inhibits formation of the cleavage complex by the unpoisoned enzyme. The D82N mutant appears to act by stabilizing the binary conformation of DNA gyrase with uncleaved DNA without direct interaction with the compounds. This provides general insight into the resistance mechanisms to antibiotics targeting bacterial type II topoisomerases.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.